Inhibitors of Akt activity

Abstract

The present invention is directed to compounds which contain a heterocyclic triazine moiety which inhibit the activity of Akt, a serine/threonine protein kinase. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for treating cancer comprising administration of the compounds of the invention.

1. A compound of the Formula A: 
       
         
           
           
               
               
           
         
       
       wherein:
 W Y is selected from CR 1 ═N, 
 
       
         
           
           
               
               
           
         
         a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1, 2 or 3; r is 0 or 1; s is 0 or 1; t is 2, 3, 4, 5 or 6; 
         Q is selected from: H, —NR 6 R 7 , aryl and heterocyclyl, said aryl and heterocyclyl which is optionally substituted with one to three R z ; 
         R 1  is independently selected from: 1) H, 2) (C═O) a O b C 1 -C 10  alkyl, 3) (C═O) a O b aryl, 4) C 2 -C 10  alkenyl, 5) C 2 -C 10  alkynyl, 6) (C═O) a O b  heterocyclyl, 7) (C═O) a O b C 3 -C 8  cycloallyl, 8) CO 2 H, 9) halo, 10) CN, 11) OH, 12) O b C 1 -C 6  perfluoroalkyl, 13) O a (C═O) b NR 6 R 7 , 14) NR c (C═O)NR 6 R 7 , 15) S(O) m R a , 16) S(O) 2 NR 6 R 7 , 17) NR c S(O) m R a , 18) oxo, 19) CHO, 20) NO 2 , 21) NR c (C═O)O b R a , 22) O(C═O)O b C 1 -C 10  alkyl, 23) O(C═O)O b C 3 -C 8  cycloalkyl, 24) O(C═O)O b aryl, 25) O(C═O)O b -heterocycle, and 26) O a —P═O(OH) 2 , said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R z ; 
         R 1′  is independently selected from: 1) H, 2) (C═O) a O b C 1 -C 10  alkyl, 3) (C═O) a O b aryl, 4) C 2 -C 10  alkenyl, 5) C 2 -C 10  alkynyl, 6) (C═O) a O b  heterocyclyl, 7) (C═O) a O b C 3 -C 8  cycloalkyl, 8) CO 2 H, 9) halo, 10) CN, 11) OH, 12) O b C 1 -C 6  perfluoroalkyl, 13) O a (C═O) b NR 6 R 7 , 14) S(O) m R a , 15) S(O) 2 NR 6 R 7 , 16) oxo, 17) CHO, 18) O(C═O)O b C 1 -C 10  alkyl, 19) O(C═O)O b C 3 -C 8  cycloalkyl, 20) O(C═O)O b aryl, 21) O(C═O)O b -heterocycle, and 22) O a —P═O(OH) 2 , said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R z ; 
         R 2  is independently selected from: 1) (C═O) a O b C 1 -C 10  alkyl, 2) (C═O) a O b aryl, 3) C 2 -C 10  alkenyl, 4) C 2 -C 10  alkynyl, 5) (C═O) a O b  heterocyclyl, 6) (C═O) a O b C 3 -C 8  cycloallyl, 7) CO 2 H, 8) halo, 9) CN, 10) OH, 11) O b C 1 -C 6  perfluoroalkyl, 12) O a (C═O) b NR 6 R 7 , 13) NR c (C═O)NR 6 R 7 , 14) S(O) m R a , 15) S(O) 2 NR 6 R 7 , 16) NR c S(O) m R a , 17) CHO, 18) NO 2 , 19) NR c (C═O)O b R a , 20) O(C═O)O b C 1 -C 10  alkyl, 21) O(C═O)O b C 3 -C 8  cycloalkyl, 22) O(C═O)O b aryl, 23) O(C═O)O b -heterocycle, and 24) O a —P═O(OH) 2 , said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one, two or three substituents selected from R z ; 
         R 3  and R 4  are independently selected from: H, C 1 -C 6 -alkyl and C 1 -C 6 -perfluoroalkyl, or 
         R 3  and R 4  are combined to form —(CH 2 ) t — wherein one of the carbon atoms is optionally replaced by a moiety selected from O, S(O) m , —N(R b )C(O)—, and 
         —N(COR a )—; 
         R 5  is independently selected from: 1) H, 2) (C═O) a O b C 1 -C 10  alkyl, 3) (C═O) a O b aryl, 4) C 2 -C 10  alkenyl, 5) C 2 -C 10  alkynyl, 6) (C═O) a O b  heterocyclyl, 7) (C═O) a O b C 3 -C 8  cycloalkyl, 8) CO 2 H, 9) halo, 10) CN, 11) OH, 12) O b C 1 -C 6  perfluoroalkyl, 13) O a (C═O) b NR 6 R 7 , 14) NR c (C═O)NR 6 R 7 , 15) S(O) m R a , 16) S(O) 2 NR 6 R 7 , 17) NR c S(O) m R a , 18) oxo, 19) CHO, 20) NO 2 , 21) O(C═O)O b C 1 -C 10  alkyl, 22) O(C═O)O b C 3 -C 8  cycloalkyl, and 23) O a —P═O(OH) 2 , said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R z ; 
         R 6  and R 7  are independently selected from: 1) H, 2) (C═O)O b R a , 3) C 1 -C 10  alkyl, 4) aryl, 5) C 2 -C 10  alkenyl, 6) C 2 -C 10  alkynyl, 7) heterocyclyl, 8) C 3 -C 8  cycloalkyl, 9) SO 2 R a , 10) (C═O)NR b   2 , 11) OH, and 12) O a —P═O(OH) 2 , said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R z , or 
         R 6  and R 7  can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 4-7 members in each ring and optionally containing, in addition to the nitrogen, one or more additional heteroatoms selected from N, O, and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R z ; 
         R z  is selected from: 1) (C═O) r O s (C 1 -C 10 )alkyl, 2) O r (C 1 -C 3 )perfluoroalkyl, 3) (C 0 -C 6 )alkylene-S(O) m R a , 4) oxo, 5) OH, 6) halo, 7) CN, 8) (C═O) r O s (C 2 -C 10 )alkenyl, 9) (C═O) r O s (C 2 -C 10 )alkynyl, 10) (C═O) r O s (C 3 -C 6 )cycloalkyl, 11) (C═O) r O s (C 0 -C 6 )alkylene-aryl, 12) (C═O) r O s (C 0 -C 6 )alkylene-heterocyclyl, 13) (C═O) r O s (C 0 -C 6 )alkylene-N(R b ) 2 , 14) C(O)R a , 15) (C 0 -C 6 )alkylene-CO 2 R a , 16) C(O)H, 17) (C 0 -C 6 )alkylene-CO 2 H, 18) C(O)N(R b ) 2 , 19) S(O) m R a , 20) S(O) 2 N(R b ) 2 , 21) NR c (C═O)O b R a , 22) O(C═O) b C 1 -C 10  alkyl, 23) O(C═O)O b C 3 -C 8  cycloalkyl, 24) O(C═O)O b aryl, 25) O(C═O)O b -heterocycle, and 26) O a —P═O(OH) 2 , said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from R b , OH, (C 1 -C 6 )alkoxy, halogen, CO 2 H, CN, O(C═O)C 1 -C 6  alkyl, oxo, N(R b ) 2  and O a —P═O(OH) 2 ; 
         R a  is: substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 2 -C 6 )alkenyl, substituted or unsubstituted (C 2 -C 6 )alkynyl, substituted or unsubstituted (C 3 -C 6 )cycloalkyl, substituted or unsubstituted aryl, (C 1 -C 6 )perfluoroalkyl, 2,2,2-trifluoroethyl, or substituted or unsubstituted heterocyclyl; and 
         R b  is: H, (C 1 -C 6 )alkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heterocyclyl, (C 3 -C 6 )cycloalkyl, (C═O)OC 1 -C 6  alkyl, (C═O)C 1 -C 6  alkyl or S(O) 2 R a ; 
         R c  is selected from: 1) H, 2) C 1 -C 10  alkyl, 3) aryl, 4) C 2 -C 10  alkenyl, 5) C 2 -C 10  alkynyl, 6) heterocyclyl, 7) C 3 -C 8  cycloalkyl, and 8) C 1 -C 6  perfluoroalkyl, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R z , or 
       
       or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
       2. The compound according to  claim 1  of the Formula B: 
       
         
           
           
               
               
           
         
       
       wherein:
 W Y is selected from CR 1 ═N, N═CR 1 ; 
 
       or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
       3. The compound according to  claim 2  wherein:
 Q is selected from: —NR 6 R 7 , phenyl and heterocyclyl which are optionally substituted with one to three R z ; 
 R a  is: (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl; and 
 R b  is: H, (C 1 -C 6 )alkyl, aryl, heterocyclyl, (C 3 -C 6 )cycloalkyl, (C═O)OC 1 -C 6  alkyl, (C═O)C 1 -C 6  alkyl or S(O) 2 R a ; 
 
       or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
       4. The compound according to  claim 3  of the Formula C: 
       
         
           
           
               
               
           
         
       
       wherein:
 Q is heterocyclyl, said heterocyclyl optionally substituted with 1 to 3 R z ; 
 R 2  is independently selected from: 1) C 1 -C 6  alkyl, 2) aryl, 3) heterocyclyl, 4) CO 2 H, 5) halo, 6) CN, 7) OH, 8) S(O) 2 NR 6 R 7 , and 9) O a —P═O(OH) 2 , said alkyl, aryl and heterocyclyl optionally substituted with one, two or three substituents selected from R z ; 
 
       or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
       5. A compound which is selected from:
 1-(1-{4-[3-(1,3-oxazol-2-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(6-phenyl-3-pyrimidin-2-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[3-(1H-imidazol-2-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[3-(1-methyl-1H-pyrazol-5-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[6-phenyl-3-(1H-pyrazol-5-yl)-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[6-phenyl-3-(1H-pyrazol-5-yl)-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[3-(1-methyl-1H-pyrazol-4-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[3-(1-methyl-1H-imidazol-2-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(6-phenyl-3-tetrahydrofuran-3-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(6-phenyl-3-tetrahydrofuran-2-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(6-phenyl-3-thien-2-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-(4-[3-(4-methylmorpholin-3-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-(4-[3-(1-acetylazetidin-3-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(6-phenyl-3-pyridin-2-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(6-phenyl-3-pyridin-3-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(6-phenyl-3-pyridin-4-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[3-(morpholin-4-ylmethyl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[6-phenyl-3-(1,3-thiazol-2-yl)-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[6-phenyl-3-(1,3-thiazol-5-yl)-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[6-phenyl-3-1H-1,2,3-triazol-5-yl)-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[6-phenyl-3-(1,3-thiazol-4-yl)-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[3-(1,1′-biphenyl-4-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(2-methyl-3-oxo-6-phenyl-2,3-dihydro-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(2-methyl-3-oxo-5-phenyl-2,3-dihydro-1,2,4-triazin-6-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; and 
 1-(1-{4-[3-(methylthio)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 or a pharmaceutically acceptable salt or a stereoisomer thereof. 
 
     
     
       6. The TFA salt of a compound according to  claim 1  which is:
 1-(1-{4-[3-(1,3-oxazol-2-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(6-phenyl-3-pyrimidin-2-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-1-{4-[3-(1H-imidazol-2-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[3-(1-methyl-1H-pyrazol-5-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[6-phenyl-3-(1H-pyrazol-5-yl)-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[6-phenyl-3-(1H-pyrazol-5-yl)-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[3-(1-methyl-1H-pyrazol-4-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[3-(1-methyl-1H-imidazol-2-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-6-phenyl-3-tetrahydrofuran-3-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-6-phenyl-3-tetrahydrofuran-2-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(6-phenyl-3-thien-2-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[3-(4-methylmorpholin-3-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[3-(1-acetylazetidin-3-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(6-phenyl-3-pyridin-2-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(6-phenyl-3-pyridin-3-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(6-phenyl-3-pyridin-4-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[3-(morpholin-4-ylmethyl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[6-phenyl-3-(1,3-thiazol-2-yl)-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[6-phenyl-3-(1,3-thiazol-5-yl)-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[6-phenyl-3-(1H-1,2,3-triazol-5-yl)-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[6-phenyl-3-(1,3-thiazol-4-yl)-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[3-(1,1′-biphenyl-4-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(2-methyl-3-oxo-6-phenyl-2,3-dihydro-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-{1-[4-(2-methyl-3-oxo-5-phenyl-2,3-dihydro-1,2,4-triazin-6-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; and 
 1-1-{4-[3-(methylthio)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 
       or a stereoisomer thereof. 
     
     
       7. A compound according to  claim 5  which is selected from:
 1-{1-[4-(6-phenyl-3-pyrimidin-2-yl-1,2,4-triazin-5-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[6-phenyl-3-(1H-1,2,3-triazol-5-yl)-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 1-(1-{4-[6-phenyl-3-(1,3-thiazol-4-yl)-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; and 
 1-(1-{4-[3-1,1′-biphenyl-4-yl)-6-phenyl-1,2,4-triazin-5-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; 
 
       or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
       8. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of  claim 1 . 
     
     
       9. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of  claim 5 . 
     
     
       10. The composition of  claim 8  further comprising a second compound selected from: 1) an estrogen receptor modulator, 2) an androgen receptor modulator, 3) a retinoid receptor modulator, 4) a cytotoxic agent, 5) an antiproliferative agent, 6) a prenyl-protein transferase inhibitor, 7) an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor, 10) an angiogenesis inhibitor, 11) a PPAR-γ agonist, 12) a PPAR-δ agonist, 13) an inhibitor of cell proliferation and survival signaling, and 14) an agent that interferes with a cell cycle checkpoint. 
     
     
       11. A method for treating breast cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of  claim 1 .